DESCRIPTION: (Applicant's Abstract) Cocaine abuse has reached epidemic proportions in the United States and has emerged as a major cause of life-threatening cardiovascular emergencies, including ventricular arrhythmias, acute myocardial infarcts, and hypertensive crises. Although these emergencies clearly are related to excessive adrenergic stimulation of the cardiovascular system, our understanding of the underlying mechanisms mediating cocaine's sympathomimetic actions is far from complete. The prevailing view is that cocaine blocks norepinephrine reuptake in sympathetic nerve terminals, thereby increasing the concentration of norepinephrine in the synaptic cleft. However, an emerging body of experimental animal literature suggests that cocaine can profoundly alter the central regulation of sympathetic nerve activity (SNA), although there is no consensus as to how this occurs. Cocaine has been suggested to both (a) decrease SNA centrally and (b) increase SNA either centrally or through baroreflex inhibition. All the available data comes from studies in anesthetized, decerebrate, or ex vivo animal preparations and the effect of cocaine on SNA in humans is unknown. The ability to measure SNA directly with microelectrodes provides the unique opportunity to test these different hypotheses in conscious humans. Based on our preliminary data, the aim of this proposal is to test two novel major hypotheses: (1) In conscious humans, the direct effect of cocaine is to increase, not decrease, SNA. (2) Sinoaortic baroreflexes are not attenuated by cocaine but rather they play a pivotal role in modulating cocaine-induced sympathetic excitation. In addition to testing these novel hypotheses, an additional aim is to test the more traditional hypothesis that in humans inhibition of norepinephrine reuptake in peripheral sympathetic nerve terminals mediates the sympathomimetic effects of cocaine on the heart and peripheral circulation. The distinctive features of this proposal include: 1) state-of-the-art neurophysiologic and cardiac catheterization techniques to study the effects of cocaine on neurocirculatory regulation in conscious humans; and 2) the focus on modulation of central sympathetic outflow by cocaine, which traditionally has been viewed as a peripherally-acting indirect sympatho-mimetic. Given the large species differences in the cardiovascular actions of cocaine and the confounding effects of general anesthesia in animal preparations, these human studies will fill in large gaps in our understanding of the underlying mechanisms mediating the sympathomimetic actions of cocaine on the human cardiovascular system.